The present invention relates to a process for preparing semi-synthetic statins and to intermediates formed during said process.
It is well known that certain mevalonate derivatives are active as hypercholesterolemic agents, which function by limiting cholesterol biosynthesis by inhibiting the enzyme HMG-CoA reductase. These mevalonate derivatives are the naturally occurring fungal metabolites lovastatin and compactin. Semi-synthetic and synthetic analogs thereof are also active.
The naturally occurring compounds lovastatin and compactin posess a 2-methylbutyrate side chain at the 8-position of the hexahydronaphthalene ring system. Analogs with a 2,2-dimethylbutyrate moiety at this position, such as simvastatin, appear to be more effective inhibitors of HMG-CoA reductase.
These compounds can be synthesized from the naturally occurring compounds. In principle, there are two possible routes for the introduction of an extra .alpha.methyl group in the 8-acyl side chain which are:
1. direct alkylation of the 2-methylbutyrate side chain, and PA0 2. removal of the 2-methylbutyrate side chain and introduction of a 2,2-dimethyl butyrate chain.
The main advantage of the direct alkylation route is the relatively high yields that can be obtained. However, there are several drawbacks. Direct methylation of unprotected lovastatin (U.S. Pat. No. 4,582,915) results in a rather impure simvastatin, containing a relatively high amount of unconverted lovastatin and many byproducts. Therefore, protection of the pyranone ring is required. Reduction of the byproducts was achieved by protecting the pyranone ring of lovastatin with t-butyl dimethyl silyl chloride prior to the alkylation (European patent EP299656). However, this is a very expensive protecting group. A less expensive protecting group is boronic acid as disclosed in international patent application WO 95/13283.
Nevertheless, this route still suffers from the fact that it is difficult to obtain a complete conversion of the 2-methylbutyrate side chain into the 2,2-dimethyl butyrate side chain. Therefore, an additional purification is necessary; for example, base hydrolysis of the remaining lovastatin to triol acid with NaOH or LiOH, in which part of the simvastatin is hydrolysed, followed by crystallization. Alternatively, selective enzymatic hydrolysis of lovastatin (U.S. Pat No. 5,223,415) may be utilized. However, these extra purification steps will reduce the yield, and make the process less efficient.
The second route, wherein the 2-methyl butyrate side chain is completely removed and another side chain is added, offers an intrinsically better quality product, as the separation of the hydrolyzed product and the esterified product is much easier to achieve compared to the unreacted starting material and the methylated product.
In U.S. Pat No. 4,293,496, the removal of the 2-methyl butyrate side chain is achieved by base hydrolysis of lovastatin with an alkali metal hydroxide, preferably LiOH. This reaction requires long processing time (50-72 hours while refluxing) or rather stringent conditions (120.degree. C.-180.degree. C.) if shorter processing times are used.
In U.S. Pat No. 4,444,784, the introduction of a new side chain to the hydrolyzed lovastatin is disclosed. It involves several separate steps: relactonization of the mevinic acid, protection of the hydroxy group in the pyranone ring by reaction with t-butyl dimethyl silyl chloride, esterification with 2,2-dimethyl butyric acid and deprotection of the hydroxy group of the pyranone ring. The main disadvantages of this process route are the low yields, and the use of an expensive protecting group, viz, t-butyl dimethyl silyl chloride.
A much less expensive protecting group is disclosed in U.S. Pat. 5,159,104. Instead of the t-butyl dimethyl silyl chloride protection of the OH-group in the pyranone ring, the OH-group was esterified with an acetic anhydride or an acylhalide. However, this process still suffers from a poor yield.
The present invention thus provides a new rather inexpensive, crystalline intermediate which can be used in both synthesis routes. In addition, a novel, quick and less expensive process for the quantitative removal of the 2-methyl butyryl side chain and addition of another side chain, is disclosed, including novel, crystalline intermediates for the preparation of semi-synthetic lovastatin and compactin intermediates. Further, a much higher yield for the removal of the side chain, about 95% was obtained compared to the yield of about 65% obtained in a comparable process as described by Askin et al. in J. Org. Chem. 1991, vol. 56, pages 4929-4932. Furthermore, by the application of the process of the present invention for the synthesis of semisynthetic statins, for example, simvastatin, the use of the carcinogen methyliodide is avoided, which is required in the direct methylation route.
The process of the present invention comprises a surprisingly selective removal of the 8'(R.sub.3 ')-side chain, for example, the 2-methyl butyryl side chain in lovastatin, thus forming a triol acid intermediate and another alcohol, by reduction with a reducing agent such as LiAlH.sub.4 or a Grignard reagent, or to a triol acid intermediate and an amide by reaction with an amine. During this reaction, the starting material is quantitatively converted into the triol acid intermediate, which offers excellent possibilities for the introduction of various side chains.